Targeting PI3Kγ overcomes myeloid cell–mediated resistance to immune checkpoint blockade.

  • Major finding: Targeting PI3Kγ overcomes myeloid cell–mediated resistance to immune checkpoint blockade.

  • Mechanism: PI3Kγ inhibition promotes an inflammatory myeloid cell phenotype and T-cell antitumor activity.

  • Impact: PI3Kγ inhibitors warrant further investigation in tumors with suppressive myeloid cell infiltration.

Immune checkpoint blockade promotes durable responses in multiple tumor types, but many tumors do not respond. The infiltration of immune-suppressive tumor-associated myeloid cells (TAMC) is associated with resistance and a poor prognosis, suggesting that immune checkpoint inhibitors will need to be combined with therapeutics designed to target the tumor immune landscape to combat resistance. De Henau and colleagues found that 4T1 breast carcinoma xenografts were resistant to immune checkpoint blockade with anti–PD-1 or anti-CTLA4 antibodies, whereas B16-F10 melanoma xenografts were more responsive to checkpoint blockade. The 4T1 tumors exhibited increased myeloid cell infiltration and fewer activated CD8+ T cells compared with B16-F10 tumors. However, expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in B16-F10 tumors (B16-GMCSF) recruited suppressive myeloid cells to the tumors and rendered them insensitive to immune checkpoint blockade, further supporting a critical role for suppressive myeloid cells in promoting resistance to immune checkpoint blockade. The gamma isoform of phosphoinositide 3-kinase (PI3Kγ) has been shown to be highly expressed in myeloid cells and to promote tumor growth, suggesting it as a possible target to overcome resistance. Accordingly, treatment with the selective PI3Kγ inhibitor IPI-549 alone reduced tumor growth in 4T1, B16-GMCSF, and several other tumor models with high levels of myeloid cell infiltration, but not in B16-F10 tumors with few suppressive TAMCs. Moreover, IPI-549 promoted the activation of inflammatory M1-like macrophages over immunosuppressive M2-like macrophages and enhanced T-cell antitumor activity. Additionally, IPI-549 upregulated expression of PD-1 and CTLA4 on CD8+ T cells, and, consistent with these findings, IPI-549 in combination with anti-CTLA4 or anti–PD-1 reduced tumor size more than IPI-549 alone in B16-GMCSF xenografts. Collectively, these results suggest that PI3Kγ inhibition may overcome resistance to immune checkpoint blockade in tumors with high infiltration by suppressive TAMCs, and support further clinical investigation with IPI-549, which is currently being studied in a phase I clinical trial.

De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 2016;539:443–7.

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